Use Of Polyether-Based And Vinyl Monomer-Based Copolymers As Binders For Dosing Forms Comprising Solid Active Ingredients

ABSTRACT

The use of water-soluble or water-dispersible copolymers which are obtained by free radical-initiated polymerization of a mixture of
         i) 30 to 80% by weight N-vinyllactam,   ii) 10 to 50% by weight vinylacetate and   iii) 10 to 50% by weight of a polyether,
 
with the proviso that the total of i), ii) and iii) is equal to 100% by weight, as binders for producing solid active ingredient-containing dosage forms.

The present invention relates to the use of copolymers which are obtained by polymerizing vinyl acetate and N-vinyllactams in the presence of a polyether as binders, especially as dry binders, for solid active ingredient-containing dosage forms, especially tablets.

Binders improve the compressibility of active ingredient-containing formulations to solid dosage forms by improving the particle adhesion.

Criteria for the standard of quality when testing compressed dosage forms such as tablets are according to the European Pharmacopoeia the uniformity of mass (weight uniformity), resistance to crushing, friability and disintegration.

Cellulose powders, for example microcrystalline or microfine celluloses, result in very hard tablets, but adversely affect the flowability of the mixture for tableting.

Further binders such as hydroxypropylmethylcelluloses or polyvinylpyrrolidones are very effective wet binders.

Dry binders suitable for granulation without addition of solvents or direct compression are hydroxypropylcelluloses or copovidone (copolymer of N-vinylpyrrolidone and vinyl acetate in the ratio 60:40 by weight).

The previously disclosed binders, especially those suitable as dry binders, are frequently able to satisfy the various criteria for the standards of quality only in part. Thus, tablet strength and disintegration time often show antipodal behavior. The friability, that is the attrition, may also be unsatisfactorily high both for soft tablets through edge attrition and for very hard tablets through capping tendencies.

The object therefore was to provide novel and improved binders, especially dry binders, for pharmaceutical, cosmetic, food product, agrotechnical or other industrial applications which show improved properties in terms of the resistance to crushing and friability of the dosage forms.

WO 2007/051743 discloses the use of copolymers obtained by polymerizing N-vinyllactam, vinyl acetate and polyethers as solubilizers for active ingredients which are slightly soluble in water.

The object has been achieved according to the invention by the use of water-soluble or water-dispersible copolymers which are obtained by free radical-initiated polymerization of a mixture of)

-   -   30 to 80% by weight of N-vinyllactam,     -   ii) 10 to 50% by weight of vinyl acetate and     -   iii) 10 to 50% by weight of a polyether,         with the proviso that the total of i), ii) and iii) is equal to         100% by weight, es binders for producing solid active         ingredient-containing dosage forms.

Preferred polymers are obtained from:

-   -   i) 30 to 70% by weight of N-vinyllactam     -   ii) 15 to 35% by weight of vinyl acetate, and     -   iii) 10 to 35% by weight of a polyether.

Particularly preferred polymers are obtained from:

-   -   i) 40 to 60% by weight of N-vinyllactam     -   ii) 15 to 35% by weight of vinyl acetate     -   iii) 10 to 30% by weight of a polyether.

The proviso that the total of components i), ii), and iii) equals 100% by weight also applies to the preferred and particularly preferred compositions.

Suitable as N-vinyllactam are N-vinylcaprolactam or N-vinylpyrrolidone or mixtures thereof. N-Vinylcaprolactam is preferably used.

Suitable polyethers are preferably polyalkylene glycols. The polyalkylene glycols may have molecular weights of from 1000 to 100 000 D [daltons], preferably 1500 to 35 000 D, particularly preferably 1500 to 10 000 D. The molecular weights are determined on the basis of the OH value measured as specified in DIN 53240.

Suitable polyalkylene glycols which are particularly preferred are polyethylene glycols. Also suitable are polypropylene glycols, polytetrahydrofurans or polybutylene glycols, which are obtained from 2-ethyloxirane or 2,3-dimethyloxirane.

Suitable polyethers are also random or block copolymers of polyalkylene glycols obtained from ethylene oxide, propylene oxide and butylene oxides, such as, for example, polyethylene glycol-polypropylene glycol block copolymers. The block copolymers may be of the AB or ABA type.

The preferred polyalkylene glycols also include those alkylated on one or both terminal OH groups. Suitable alkyl radicals are branched or unbranched C₁- to C₂₂-alkyl radicals, preferably C₁-C₁₈-alkyl radicals, for example methyl, ethyl, n-butyl, isobutyl, pentyl, hexyl, octyl, nonyl, decyl, dodecyl, tridecyl or octadecyl radicals.

General processes for preparing the copolymers of the invention are known per se. The preparation takes place by free radical-Initiated polymerization, preferably solution polymerization, in nonaqueous, organic solvents or in mixed nonaqueous/aqueous solvents. The preparation of the copolymers and their conversion into the powder form is described in detail in WO 2007/051743, the disclosure of which concerning the preparation of the copolymers is hereby incorporated by reference.

The polymers have Fikentscher K values in the range from 10 to 60, preferably 15 to 40, measured in a 1% by weight ethanolic solution.

The polymers are suitable according to the invention as binders for producing solid dosage forms, especially as binders for producing tablets.

The polymers have glass transition temperatures in the range from 30 to 120° C., preferably from 50 to 80° C.

The use as dry binders for powder mixtures for direct tableting is preferred.

The polymers are, however, also suitable for use in wet granulation, fluidized-bed granulation or dry granulation.

In the case of wet granulation, the binder may be employed in the form of an aqueous or else organic solution comprising preferably 1 to 30% by weight of binder. The polymer solution may be granulated with the other ingredients in, for example, a mixer or kneading device.

In the case of fluidized-bed granulation, the binder in the form of a solution, preferably an aqueous solution, may be sprayed onto a fluid bed of components in powder form, and agglomeration takes place. Located within the fluid bed there may be the active pharmaceutical ingredients and/or further pharmaceutical excipients.

According to one other preferred embodiment, the polymers are also suitable for processing by sinter granulation. In this case the polymers are softened by the energy input from the mixing operation, and/or as a result of elevated temperature, and as a result of this softening there is agglomeration of the components employed. As a result of the softening and subsequent solidification by cooling, solid-material bridges are formed. The operation may be conducted such that there is surface softening or partial softening of the polymer particles. It is also possible to operate the sinter granulation in such a way that there is complete softening of the polymers. Complete softening may be advisable if particularly strong binder bridges are desired.

Sinter granulation may take place in a heatable mixer, kneading device or screw extruder.

In the case of processing in a screw extruder, the extruder is used without a die plate, in other words in open mode. The process takes place without pressure being applied. Through a suitable choice of screw configuration it is possible to set the particle size of the granules with a narrow particle size distribution. The screw configuration to be selected for this purpose, as a function of the mixture used, can be determined by the skilled person, by means of a few suitable tests.

Sinter granulation may take place at temperatures of 50 to 120° C., preferably 70 to 100° C. The temperature particularly suitable is dependent on the composition of the mixture. Where plasticizing substances are included in the processing operation, lower temperatures may optionally be selected.

Irrespective of the granulating method used, it is possible to incorporate, for example, the active pharmaceutical ingredients and also other pharmaceutical excipients, such as surface-active compounds, further binders, fillers, acidifiers, buffers, flavors and fragrances, stabilizers or colorants into the granules.

To produce the solid dosage forms, the active pharmaceutical ingredient may be processed intragranularly or extragranularly. Thus it is possible to produce granules which comprise further pharmaceutical excipients but no active ingredient, and then to mix these granules with the active ingredients. It is also possible to incorporate an active ingredient both intragranularly and extragranularly. Combinations of the different active ingredients may also be used. In the case of active ingredients which are incompatible with one another, one may be processed intragranularly and the other extragranularly.

The granule particles may have average particle sizes of 100 to 1000 μm, preferably 200 to 600 μm. In the granule particles the fraction of binder according to the invention may be 1 to 60%, preferably 5 to 30% by weight.

The binder of the invention can be employed in amounts of from 1 to 20% by weight, preferably 1 to 10% by weight, based on the total weight of the dosage form.

Pharmaceutical preparations for producing solid dosage forms may, besides the binders of the invention, also comprise conventional pharmaceutical excipients such as fillers, disintegrants, coloring agents, flavorings, film-forming water-insoluble polymers, thickeners or surface-active agents, and further conventional binders in the amounts conventional for his purpose.

Examples of suitable fillers are sugars, sugar alcohols or mixtures thereof. Suitable sugars or sugar alcohols are trehalose, mannitol, erythritol, isomalt, maltitol, lactitol, xylitol, sorbitol. Furthermore, inorganic substances may also be used as fillers. Suitable in this case are dicalcium and tricalcium phosphates.

As disintegrants can be employed in amounts of from 1 to 25% by weight, preferably 2 to 15% by weight, particularly preferably 3 to 10% by weight. Such disintegrants are water-insoluble but not film-forming. Examples of suitable disintegrants are crospovidone, a crosslinked polymer of N-vinylpyrrolidone. Also suitable is croscarme/lose, a crosslinked carboxymethylceliulose, where croscarmellose also means according to the invention the sodium and calcium salts thereof. Also suitable is sodium carboxymethyl starch. L-Hydroxypropylcellulose, preferably with 5 to 16% hydroxypropyl groups, is likewise suitable.

Further excipients which can be employed are water-insoluble polymers which are insoluble in the pH range from 1 to 14, that is have a pH-independent insolubility in water at every pH. However, also suitable are polymers which are insoluble in water at every pH in the pH range from 6 to 14, but are soluble in an acidic medium. The polymers may be film-forming polymers. Film-forming means in this connection that the polymers have a minimum film-forming temperature of from −20 to +150° C., preferably 0 to 100° C., in aqueous dispersion. Suitable polymers are polyvinyl acetate, ethylcellulose, methyl methacrylate-ethyl acrylate copolymers, ethyl acrylate-methyl methacrylate-trimethylammoniumethyl methacrylate terpolymers, butyl methacrylate-methyl methacrylate-dimethylaminoethyl methacrylate terpolymers. The acrylate-methacrylate copolymers are described in detail in the European Pharmacopoeia as polyacrylate dispersion 30%, in the USP as ammonio methacrylate copolymer and in JPE as aminoalkyl-methacrylate copolymer E. Polyvinyl acetate can be employed as aqueous dispersion with solids contents of from 10 to 45% by weight. Additionally preferred is polyvinyl acetate with a molecular weight of between 100 000 and 1 000 000 daltons, particularly preferably between 200 000 and 800 000 daltons,

The formulations may further comprise as components additional water-soluble polymers in amounts of from 0 to 15% by weight. Suitable water-soluble polymers are for example polyvinylpyrrolidones, vinylpyrrolidone-vinyl acetate copolymers, polyvinyl alcohols, polyvinyl alcohol-polyethylene glycol graft copolymers, polyethylene glycols or ethylene glycol-propylene glycol block copolymers.

It is further possible to employ thickeners such as methylcellulose, hydroxypropyl-methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carrageenans, pectins, xanthans or alginates. It is possible by adding thickeners such as, for example, high molecular weight polysaccharides for the mouthfeel to be additionally improved by increasing the softness and the sensation of volume.

It is possible if desired to employ further pharmaceutically customary excipients in amounts of from 0 to 15% by weight, for example such as acidifiers, buffer substances, sweeteners, flavorings, flavor enhancers and colorants. The following substances are particularly suitable in this connection: citric acid, tartaric acid, ascorbic acid, sodium dihydrogenphosphate, cyclamate, saccharin Na, aspartame, menthol, peppermint flavor, fruit flavors, vanilla flavor, glutamate, riboflavin, beta carotene, water-soluble colorants, finely divided color lakes.

In addition, surface-active compounds can also be added, for example sodium lauryl sulfate, dioctyl sulfosuccinate, alkoxylated sorbitan esters such as polysorbate 80, polyalkoxylated derivatives of castor oil or hydrogenated castor oil, for example Cremophor® RH 40, alkoxylated fatty acids, alkoxylated hydroxy fatty acids, alkoxylated fatty alcohols, alkali metal salts of fatty acids and lecithins.

It is further possible to add pigments such as iron oxides, titanium dioxide, colloidal or precipitated silica, calcium carbonates or calcium phosphates.

The finished tablets can also be provided with conventional coatings.

EXAMPLES

The angle of repose and the flow rate were determined in accordance with DIN ISO 4324. The bulk density was determined in accordance with Pharm. Eur. 5. Apparatus used: tablet tester (Kramer), tablet disintegration tester ZT 74 (ERWEKA), friability tester TAR 20 (ERWEKA)

Example 1 Dry Binder

The binding power was assessed on a polymer A, obtained from 13% by weight polyethylene glycol PEG 6000, 57% by weight N-vinylcaprolactam and 30% by weight vinyl acetate with a K value of 35.

For comparison, the binding power of povidone K30 (polyvinylpyrrolidone of K value 30) and of copovidone (copolymer of N-vinylpyrrolidone and vinyl acetate in a weight ratio of 60:40. K value 28; Kollidon® VA 64, BASF), and of mixtures without binder, was assessed as follows.

Assessment good moderate poor Resistance to crushing [N] >75 60-75 <60 Friability [%] <0.5 0.5-1.0 >1.0 Disintegration [min] <4 4-6 >6 Weight uniformity [%] <0.6 0.6-0.8 >0.8

The following compositions were used:

per 500 mg tablet weight 200.00 mg of ascorbic acid powder

231.25 mg of Ludipress¹⁾

50.00 mg of binder 15.00 mg of crospovidone²⁾ 1.25 mg of colloidal silicon dioxide³⁾ 2.50 mg of magnesium stearate 1) Ludipress®: formulation of 93% by weight lactose, 3.5% by weight povidone K30 (Kollidon® 30, from BASF), 3.5% by weight crospovidone 2) Crospovidone: Kollidon® CL, from BASF 3) Aeosil® 200, from Evonik

The mixture of components was passed through a sieve with a mesh width of 0.8 mm, put in a glass bottle and mixed in a Tabula mixer for 10 minutes, and compressed to tablets.

Tablet format: 12 mm diameter, beveled Compressive force: 18 kN Tableting rate: 30 rpm rotary press

The tablets were subsequently tested for their physical properties.

Polymer A according Povidone No to the Binder K30 Copovidone binder invention Resistance to 65 90 49 87 crushing [N] Friability [%] 0.43 1.14 3.5 (15% 0.44 breakage) Disintegration [min.sec] 1.19 1.02 0.24 2.30 Weight uniformity [%] 4.12 0.58 1.01 0.34

The binder used according to the invention therefore results in tablet resistances to crushing which are comparable to those of tablets comprising copovidone, but at the same time in particular results in distinctly lower friability.

Example 2 Wet Binder

Initial mass Composition after drying Formula [g] [% by weight] Calcium 350.00 80.8 hydrogenphosphate Lactose 50.00 11.5 Binder 12.40 2.9 DI water 55.00 — Kollidon CL 18.56 4.3 Magnesium stearate 2.06 0.5

Calcium hydrogen phosphate and lactose were weighed out into a Diosna mixer (Diosna P 1/6 (2 L stirring vessel)) and the mixture was mixed for 1 minute (200 rpm stirrer/2200 rpm chopper). An aqueous solution of binder with a strength of 18.4% by weight was added dropwise over the course of 4 minutes with continual stirring (at 200 rpm stirrer/2200 rpm dropper). Following addition of the binder solution to the mixture, mixing was continued for 2 minutes. The stirrer speed was then raised to 1500 rpm for 30 seconds, while the chopper continued to run at 2200 rpm. Thereafter the moistened mass was passed through a sieve with a mesh size of 0.8 mm, and the wet granules were dried in air on racks for 12 hours. The absolute loss of the granules on drying was determined using an IR drier to constant mass of 80° C. Subsequently Kollidon CL and magnesium stearate were added. The overall mass was passed through a sieve with a mesh size of 0.8 mm and introduced into a glass bottle, which was sealed, followed by mixing for 5 minutes in a Turbula mixer (Turbula mixer T2, Willy A Baclofen AG).

Tablets were then produced and tested as described in Example 1.

Tablet Analysis:

Pressing Resistance to Friability Disintegration pressure Binder crushing [N] [%] [s] 18 kN Inventive, polymer A 103 0.13 31 Kollidon VA 64 83 0.37 38 Kollidon 30 95 0.18 35 Kollidon 90 F 109 0.15 117

The inventive polymer used, in comparison to known binders, had a higher binding strength in tandem with an improved friability and more rapid disintegration.

Example 3 Sintered Granules

Formula Composition [% by weight] Polymer A 50 Lactose 45 PEG 400 5

The polymer and the lactose (Granulac® 230, average particle size 27 μm) were weighed out into a Stephan mixer (UMC 5). The product container was heated at 95° C. by means of a double jacket design and connected oil bath. This mixture was mixed for 5 minutes (with a stirrer speed of 1000 rpm). After a homogenous mixture had been achieved, polyethylene glycol (PEG 400; Lutrol® E 400, BASF SE) was added dropwise to the mixture, and mixing was continued at the same speed for a further 20 minutes. The finished granules were subsequently passed through a sieve (mesh size 1000 μm) to remove oversize.

The resultant granules were characterized and showed successful agglomeration of the lactose. The average particle diameter increased from 27 μm (Granulac 230) to 396 μm (lactose granules with polymer A).

Surprisingly, the granules formed had virtually no fine fraction, which suggests uniform agglomeration behavior. This is evidenced by the d₁₀ value of 228 μm, which means that less than 10% by weight of the particles have a particle size of less than 228 μm. The bulk density of the granules was 0.63 g/ml as determined using the bulk/tamp volumeter in accordance with Ph. Eur. The flow behavior of the granules, determined by means of a Pfrengle funnel, gave an angle of repose of 26.6° and a flow time of 7.2 seconds.

The granules were subsequently compressed to form tablets. Prior to the tableting of the finished granules, 5% by weight of disintegrant (crospovidone; Kollidon® CL) and 0.5% by weight of lubricant (magnesium stearate) were added. The total mass was passed again through a sieve with a mesh size of 1.0 mm and introduced into a glass bottle, which was sealed, and mixing took place for 5 minutes in a Turbula mixer. The pressing mixture was compressed on an eccentric press (EK0 eccentric press) at 18 kN to give tablets with a size of 12 mm.

The properties of the tablets were as follows:

Resistance to crushing: 80 N

Friability: 0.2% Disintegration: 50 s Example 4 Sintered Granules; Percentages [% By Weight]

Formulation 1 Formulation 2 Formulation 3 Formulation 4 50% polymer A 50% polymer A 50% polymer A 40% polymer A 30% lactose 30% lactose 25% lactose 35% lactose 20% fenofibrate 15% itraconazole 20% cinnarizine 20% cinnarizine —  5% PEG 400 PEG 5% 600  5% PEG 600

The granules will be produced in a twin-screw extruder with a screw diameter of 16 mm (L/D ratio=40) from ThermoFisher Polylab, which is operated without pressurization and with an open head. Granulation took place at a screw speed of 100 rpm with a barrel temperature (from the 2^(nd) barrel onward) of 80° C.

Formulation Formulation Formulation Formulation 1 2 3 4 Angle of 28° 30° 30° 31° repose Flow rate 8 sec 7 sec 8.1 sec 7.5 sec Bulk density 0.6 g/ml 0.65 g/ml 0.55 g/ml 0.58 g/ml Average 350 μm 420 μm 342 μm 380 μm particle diameter 

1. A solid active ingredient-containing dosage form comprising binders that include water-soluble or water-dispersible copolymers which are obtained by free radical-initiated polymerization of a mixture of i) 30 to 80% by weight of N-vinyllactam, ii) 10 to 50% by weight of vinyl acetate and iii) 10 to 50% by weight of a polyether, with the proviso that the total of i), ii) and iii) is equal to 100% by weight.
 2. The solid active ingredient-containing dosage form according to claim 1, wherein the copolymers are obtained from i) 30 to 70% by weight of N-vinyllactam ii) 15 to 35% by weight of vinyl acetate, and iii) 10 to 35% by weight of a polyether, is employed.
 3. The solid active ingredient-containing dosage form according to claim 2, wherein the copolymers are obtained from i) 40 to 60% by weight of N-vinyllactam ii) 15 to 35% by weight of vinyl acetate iii) 10 to 30% by weight of a polyether.
 4. The solid active ingredient-containing dosage form according to claim 1, in the form of a tablets.
 5. The solid active ingredient-containing dosage form according to claim 1, comprising the binders in an amount of from 1 to 20% by weight based on the total weight of the dosage form.
 6. The solid active ingredient-containing dosage form according to claim 5, comprising the binders in an amount of from 1 to 10% by weight in the dosage forms.
 7. The solid active ingredient-containing dosage form according to claim 1, wherein the binders are employed as dry binders.
 8. The solid active ingredient-containing dosage form according to claim 7, wherein the binders are employed as dry binders for direct tableting.
 9. The solid active ingredient-containing dosage form according to claim 1, wherein the binders are employed in the form of wet granules or fluidized-bed granules.
 10. The solid active ingredient-containing dosage form according to claim 1, wherein the binders are in the form of sintered granules.
 11. The solid active ingredient-containing dosage form according to claim 10, where the sintered granules are obtained at temperatures of 50 to 100° C.
 12. The solid active ingredient-containing dosage form according to claim 11, where the sintered granules are obtained at temperatures of 70 to 100° C.
 13. The solid active ingredient-containing dosage form according to claim 1, where the binders are granulated in the presence of further pharmaceutical excipients.
 14. The solid active ingredient-containing dosage form according to claim 1, where the binders are granulated in the presence of active pharmaceutical ingredients.
 15. A process for producing a solid pharmaceutical dosage form, which comprises mixing, as binders, water-soluble or water-dispersible copolymers which are obtained by free radical-initiated polymerization of a mixture of i) 30 to 80% by weight of N-vinyllactam, ii) 10 to 50% by weight of vinyl acetate and iii) 10 to 50% by weight of a polyether, with the proviso that the sum of i), ii) and iii) is equal to 100% by weight, with active pharmaceutical ingredients and optionally further pharmaceutical excipients, and subsequently converting the mixture into the solid pharmaceutical dosage form.
 16. The process according to claim 15, wherein the binders are mixed dry with the active pharmaceutical ingredients and optionally the further pharmaceutical excipients to form a dry mixture, and the dry mixture is converted into the solid pharmaceutical dosage forms.
 17. The process according to claim 16, wherein the binders are incorporated in the form of granules into the solid pharmaceutical dosage form.
 18. The process according to claim 17, wherein the granules are obtained by wet granulation, fluidized-bed granulation or sinter granulation.
 19. The process according to claim 17, wherein further pharmaceutical excipients are incorporated into the granules.
 20. The process according to claim 17, wherein the active pharmaceutical ingredients are incorporated into the granules.
 21. The process according to claim 15, wherein the mixture of the binders, the active pharmaceutical ingredients and the optionally further pharmaceutical excipients is converted by compression into the solid dosage form. 